title: The duration of pacing-induced atrial fibrillation is reduced in vivo by inhibition of small conductance Ca(2+)-activated K(+) channels.
abstract: Atrial fibrillation (AF) is associated with increased morbidity and is in addition the most prevalent cardiac arrhythmia. Compounds used in pharmacological treatment has traditionally been divided into Na(+) channel inhibitors, β-blockers, K(+) channel inhibitors, and Ca(2+) channel inhibitors, whereas newer multichannel blockers such as amiodarone and ranolazine have been introduced later. This study was devoted to the evaluation of an acute pacing-induced in vivo model of AF in rats. Antiarrhythmic effects of well-known compounds such as lidocaine, dofetilide, and ranolazine were confirmed in this model. In addition, antiarrhythmic effects of different inhibitors of Ca(2+)-activated small conductance K(+) (SK) channels were demonstrated. Intravenous application of 5 mg/kg of the negative SK channel modulator NS8593 reduced AF duration by 64.5%, and the lowest significantly effective dose was 1.5 mg/kg. A dose-effect relationship was established based on 6 different dose groups. Furthermore, it was demonstrated that the antiarrhythmic effect of NS8593 and other tested drugs was associated with an increase in atrial effective refractory period. The functional role of SK channels was confirmed by 2 other SK channel inhibitors, UCL1684 and apamin, thereby confirming the hypothesis that these channels might constitute a new promising target for antiarrhythmic treatment.
authors.affiliation: Membrane Protein Physiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lasse
authors.initials: L
authors.lastname: Skibsbye
authors.forename: Jonas Goldin
authors.initials: JG
authors.lastname: Diness
authors.forename: Ulrik Svane
authors.initials: US
authors.lastname: Sørensen
authors.forename: Rie Schultz
authors.initials: RS
authors.lastname: Hansen
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
mesh_terms: D015057:1-Naphthylamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D000473:Alkanes / Q000627:therapeutic use; D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001030:Apamin / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019476:Insect Proteins / Q000627:therapeutic use; D008297:Male; D058990:Molecular Targeted Therapy; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D011806:Quinolinium Compounds / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: C515166:(R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine; C110349:6,10-diaza-3(1,3),8(1,4)dibenzena-1,5(1,4)diquinolinacyclodecaphane; D000473:Alkanes; D000889:Anti-Arrhythmia Agents; D019476:Insect Proteins; D026902:Potassium Channel Blockers; D011806:Quinolinium Compounds; D051640:Small-Conductance Calcium-Activated Potassium Channels; D001030:Apamin; D015057:1-Naphthylamine